Synthesis and stereochemistry of azeto[2,1-a ]isoquinolin-2-one derivatives

Azeto[2,1-a ]isoquinolin-2-one derivatives 3-7 were prepared by the reaction of dihydro-isoquinoline 1a or 1b with the corresponding acid chloride 2a-c in the presence of triethylamine. Alternatively, 4 was obtained by the reaction of 1a and phenoxyacetic acid 2d in the presence of phosphoryl chloride


Introduction
][7] Although many methods are known for the construction of β-lactam rings, the Staudinger reaction is still the most frequently used and is considered to be the most effective method.In the standard reaction, ketenes formed by the dehydrohalogenation of acid chlorides containing an αhydrogen are added to an imine in the presence of a base.[10] By means of the above cycloaddition reactions, a great number of azeto[2,1-a]isoquinolin-2one derivatives of synthetic and pharmacological interest have been prepared.However, the stereochemistry and transformations of these azetidinone derivatives have been investigated in only a few cases. 11s a continuation of our investigations into the structure of azeto[2,1-a]isoquinolines, [12][13][14][15] the present work aimed at the preparation and structure analysis of different azeto[2,1-a]isoquinolin-2-ones.

Chemistry
7][18][19][20] Occasionally, low yields are obtained 21 or the reaction does not lead to the expected β-lactam. 22he reaction of dihydroisoquinoline 1a or 1b in dichloromethane with phenylacetyl chloride 2a failed in the presence of triethylamine at room temperature.When the reaction was carried out in refluxing toluene, azeto[2,1-a]isoquinolin-2-one derivatives 3 and 5 were obtained in good yields.Similarly, 4, 6 and 7 were prepared by the reaction of dihydroisoquinoline 1a or 1b with the corresponding acid chloride 2b or 2c.Alternatively, 4 was prepared by the reaction of 1a and phenoxyacetic acid 2d via the acid chloride generated in situ in the presence of POCl 3 (Scheme 1) 23 .

NMR spectroscopy
The relative configurations and the predominant conformation of the azetoisoquinoline skeleton were investigated with the aid of standard NMR spectroscopic methods.The studied compounds exhibited similar spectral parameter patterns, and therefore the discussion holds for all the compounds reported here, unless otherwise stated.The scalar coupling patterns for protons H-4 and H-5 reveal a rigid trans-diaxial arrangement for H-5ax and H-4ax (Table 1).At the same time, NOESY cross-peaks can be observed from the H-2΄, H-6΄ protons of Ph-9b to H-5ax and H-4eq, which proves the spatial assignment of the signals (Figure 1).The hardly detectable NOE interactions between H-2΄, H-6΄ protons of Ph-9b and H-1 suggest a cis relative configuration for Ph-9b and R 2 , although this observation cannot be regarded as an unambiguous proof for this assumption.It is interesting that, in derivative 7, the aromatic protons of the phthalimido group at 7.70 and 7.63 ppm exhibit chemical exchange broadening at ambient temperature, presumably caused by hindered rotation, which supports the cis relative configuration on C-9b and C-1 (Figure 2).At 328 K, the broadening decreases so that the multiplet pattern is observable.
Yield 78%.The physical and spectroscopic data on the product were identical to those of the product prepared by Method A.

Table 1 .
Characteristic vicinal coupling constants Figure 1.3D structure of 3, determined by NMR spectroscopy and Merck molecular force field calculations.